Introduction HPV E4 protein is synthesized as a E1^E4 fusion protein as a result of mRNA splicing. The knowledge regarding the functions of E1^E4 during the viral life cycle remains incomplete. It is safe to suggest that the protein is involved in virus release and transmission and that it is a marker of the onset of productive infection. However, the potential role of E4 as a tool to stratify cervical intraepithelial neoplasia (CIN), and to detect HPV-associated lesions that may progress towards CIN2+, has been reported in multiple publications recently. The management of CIN2 is still controversial, prompting us to investigate the correlation between E4 expression and prognosis of lesions classified as CIN2.

Methods We carried out a retrospective cohort study using the medical and histopathological records of 115 patients with CIN2 treated. E4 was detected as described previously (Griffin et al., 2015). Regression was defined as negative cytological and histological result for more than one year. Progression was defined as the appearance of histologically confirmed CIN3 during follow-up. We built Kaplan-Meier curves for progression/regression groups and compared unadjusted survival statistics using Log-rank test.

Results The cases were 28, 67, and 20 for regression, persistence, and progression, respectively. Kaplan-Meier curves showed that E4 expression was significantly difference between progression and regression (Log-rank test=p<0.001). CIN2 progressed in the E4 negative cases and regressed in the E4 positive cases.

Conclusion/Implications The E4 expression was correlated with progression/regression of CIN2. These data suggest that the HPV E4 expression is a candidate biomarker for prognosis of CIN2.